FDA Advises Against Submission for ALS Stem Cell Therapy

The FDA has advised against submission of a biologics license application (BLA) for the autologous mesenchymal stem cells (MSC) therapy NurOwn as a treatment for patients with amyotrophic lateral sclerosis (ALS) based on insufficient clinical evidence, according to a statement released by Brainstorm Cell Therapeutics, the developer of the therapy. Despite this feedback from the FDA, Brainstorm is still considering submission.

"Brainstorm will first consult with principal investigators, ALS experts, expert statisticians, regulatory advisors, and ALS advocacy groups to assess the benefit:risk of a BLA submission before making a final decision," Chaim Lebovits, CEO Brainstorm Cell Therapeutics, said in a statement.

Interim results from the phase 3 study were released in November 2020 and showed a lack of statistical significance for the MSC therapy. A 1.25-point per month improvement post-treatment in revised ALS functional rating scale (ALSFRS-R) slope was experienced by 34.7% of patients treated with NurOwn compared with 27.7% in the placebo group (P = .453). Additionally, for the secondary end point, there was a -5.52 change in ALSFRS-R from baseline to week 28 in the NurOwn arm compared with -5.88 in the placebo group (P = .693).

"We learned a lot about the efficacy and safety of NurOwn in people with ALS in this well conducted trial," co-principal investigator Merit Cudkowicz, MD, chief of Neurology and director of the Healey & AMG Center for ALS at Mass General Hospital, said in a statement. "We also learned some of the challenges with the use of ALSFRS-R at the lower end of the scale. Additional discussions with the community and sharing all the data in a peer reviewed publication are critical next steps."

NurOwn consists of MSC that have been enhanced and expanded ex vivo to secrete several neurotrophic factors (NTFs). The autologous cells, which secrete primarily GDNF, brain-derived NTF, VEGF, and hepatocyte growth factor (HGF), are administered in 3 intrathecal transplantations, each 2 months apart.

In the phase 3 study, 189 patients with rapidly progressing ALS were randomized 1:1 to 3 intrathecal administrations of NurOwn or matched placebo. Rapid progression was defined as more than a 3-point decrease in ALSFRS-R during an 18-week run-in period. Each administration of the treatment was separated by 8 weeks and patients were observed for 28 weeks following treatment.

In a prespecified subgroup analysis of those with early ALS (baseline ALSFRS-R ≤35), there was a 1.25-point per month ALSFRS-R improvement for 34.6% of those treated with NurOwn versus 15.6% with placebo (P = .288). The average change from baseline to week 28 in the early disease group was -1.77 with NurOwn versus -3.78 with placebo (P = .198). Neither of these measures passed statistically significance; however, full data from the study have yet to be released.

"ALS is a devastating disease with worse outcomes than most forms of cancer," Anthony Windebank, MD, Jean and Judith Pape Adams Professor of Neuroscience, Mayo Clinic College of Medicine and Science, said in a statement. "The clear signal in this trial that some patients with ALS respond to treatment with NurOwn is a light at the end of the tunnel. The careful study of biomarkers associated with response will help lead us forward towards a broadly effective therapy. The patients and their families who have brought us to this point are true heroes."

Biomarker analyses from cerebrospinal fluid will continue but early signs suggest activity with the therapy. At the interim analysis, there was a statistically significant increase in neurotrophic factors with NurOwn and a reduction in neurodegenerative and neuroinflammatory biomarkers, which would be in line with the mechanism of action.

"We will complete all ALS phase 3 study analyses to support scientific communication of the phase 3 data, including a peer-reviewed manuscript," Ralph Kern, MD, MHSc, president and chief medical officer Brainstorm Cell Therapeutics, said in a statement. "The results of the phase 3 clinical trial are very important, and we are confident that the analysis of key ALS disease biomarkers will contribute to our understanding of ALS. Our focus is to advance our proprietary cellular technology platform and to prioritize product development efforts based on data and business priorities."